Relationship between Celiac Disease and Refractory Idiopathic Epilepsy in Children

ObjectiveEpilepsy occurs with a yearly incidence of 40 per 100,000 children, of which more than 25% are resistant to drug therapy. Epilepsy may occur in autoimmunediseases like lupus, celiac disease and myasthenia gravis. In this study, therelationship between celiac disease and refractory epilepsy was evaluated inchildren with idiopathic epilepsy.Material & MethodsHundred-fifty-five children (mean age, 6.7±3.3 years) with idiopathic andcryptogenic epilepsy referred to the neurology clinic were studied in two groups;drug controlled epilepsy (control, 82 patients) and refractory epilepsy groups(case, 73 patients). Both groups underwent serological tissue transglutaminaseantibody measurement by ELISA. In seropositive cases, small intestine biopsywas conducted. Data analysis was performed using student's t test and 2 test.ResultsSeven (0.04%) patients had celiac disease based on a positive tissuetransglutaminase antibody and three patients (0.01%) based on a positive biopsy.Three patients (2.4%) with drug controlled epilepsy (control group) and fivewith refractory epilepsy (case group) had seropositive celiac disease (p=0.255).In the biopsy survey of six seropositive patients, one patient (1.2%) in the drugcontrolled epilepsy and two patients (2.7%) in the refractory epilepsy group hadpositive biopsy for celiac disease (p = 0.604). One seropositive patient did notcooperate for biopsy.ConclusionIf the relationship between celiac disease and epilepsy, especially in casesof symptomatic or oligosymptomatic celiac is proved, using gluten freediet increases the ability to control epilepsy particularly in refractory cases.We suggest celiac disease survey is not required in patients with idiopathicepilepsy

The liver X receptor agonist GW3965 improves recovery from mild repetitive traumatic brain injury in mice partly through apolipoprotein E.

Traumatic brain injury (TBI) increases Alzheimer's disease (AD) risk and leads to the deposition of neurofibrillary tangles and amyloid deposits similar to those found in AD. Agonists of Liver X receptors (LXRs), which regulate the expression of many genes involved in lipid homeostasis and inflammation, improve cognition and reduce neuropathology in AD mice. One pathway by which LXR agonists exert their beneficial effects is through ATP-binding cassette transporter A1 (ABCA1)-mediated lipid transport onto apolipoprotein E (apoE). To test the therapeutic utility of this pathway for TBI, we subjected male wild-type (WT) and apoE-/- mice to mild repetitive traumatic brain injury (mrTBI) followed by treatment with vehicle or the LXR agonist GW3965 at 15 mg/kg/day. GW3965 treatment restored impaired novel object recognition memory in WT but not apoE-/- mice. GW3965 did not significantly enhance the spontaneous recovery of motor deficits observed in all groups. Total soluble Aβ(40) and Aβ(42) levels were significantly elevated in WT and apoE-/- mice after injury, a response that was suppressed by GW3965 in both genotypes. WT mice showed mild but significant axonal damage at 2 d post-mrTBI, which was suppressed by GW3965. In contrast, apoE-/- mice showed severe axonal damage from 2 to 14 d after mrTBI that was unresponsive to GW3965. Because our mrTBI model does not produce significant inflammation, the beneficial effects of GW3965 we observed are unlikely to be related to reduced inflammation. Rather, our results suggest that both apoE-dependent and apoE-independent pathways contribute to the ability of GW3965 to promote recovery from mrTBI

mrTBI-induced motor impairment recovers spontaneously independent of GW3965 and apoE.

<p>Motor performance of WT (n = 38) and apoE−/− (n = 30) mice was evaluated by the accelerating rotarod task (0 to 30 rpm in 210 s). (<b>A</b>) Rotarod latencies of untreated (V, open squares) and GW3965-treated (G, black filled squares) WT mice before and following mrTBI. (<b>B</b>) Rotarod latencies of untreated (V, open circles) and GW3965-treated (G, black filled circles) apoE−/− mice before and following mrTBI. Asterisks in A and B denote significant differences between baseline and post-mrTBI latencies within each group. For both genotypes, the treatment effect was not significant at any post-TBI time point (curly brackets). (<b>C</b>) Rotarod latencies of untreated WT (open squares) and apoE−/− (open circles) mice before and following mrTBI. (<b>D</b>) Rotarod latencies of GW3965-treated WT (black filled squares) and apoE−/− (black filled circles) mice before and following mrTBI. # and § in C and D denote significant differences between the latencies of WT and apoE−/− mice at the respective time points. Cohorts were: Untreated WT mice: (1 d = 34, 2 d = 34, 7 d = 24; 14 d = 14); GW3965-treated WT mice: (1 d = 35, 2 d = 35, 7 d = 25, 14 d = 14); untreated apoE−/− mice: (1 d = 24, 2 d = 24, 7 d = 20, 14 d = 9), and GW3965-treated apoE−/− mice: (1 d = 27, 2 d = 22, 7 d = 20, 14 d = 9). Data were analyzed using two-way repeated measures ANOVA followed by a Bonferroni post hoc test. *: <i>p</i><0.05, **: <i>p</i><0.01, ***: <i>p</i><0.001, ****: <i>p</i><0.0001, #: <i>p</i><0.05, ##: <i>p</i><0.01, §§: <i>p</i><0.01.</p

GW3965 augments ABCA1 levels in WT and apoE−/− mice following mrTBI.

<p>ABCA1 protein levels were determined in ipsilateral half brains of WT (<b>A</b>) and apoE−/− (<b>B</b>) mice following mrTBI using Western blots, with representative blots shown below the graphs. Data are expressed as fold difference normalized to sham values. Data from sham animals within each genotype were pooled (grey bars). Numbers inside the bars indicate sample size. Asterisks above individual bars indicate significant difference compared to the respective sham levels. *: <i>p</i><0.05, **: <i>p</i><0.01, ***: <i>p</i><0.001, ****: <i>p</i><0.0001. Data were analyzed by two-way ANOVA followed by a Bonferroni post hoc test. Legend: S: sham V: untreated mice, open bars, G: GW3965-treated mice, black bars.</p

Microglia are not significantly activated by mrTBI in either WT or apoE−/− mice.

<p>Microglial activation in sham and injured WT and apoE−/− mice was assessed with Iba1 immunohistochemistry. The top panel depicts representative images of Iba1-stained coronal sections at approximately −1.82 mm from bregma <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0053529#pone.0053529-Paxinos1" target="_blank">[66]</a>. The bottom panel depicts 10X-magnified images of ipsilateral cortex underlying the injury site (indicated by the black rectangle). Legend: V- untreated mice, G- GW3965-treated mice.</p

Pronounced microglial activation is localized only around contused areas.

<p>In this study, approximately 4–8% of brains subjected to mrTBI showed micro contusions in the absence of gross skull fracture. The left panel shows a Iba1-stained coronal section at approximately −1.82 mm from bregma <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0053529#pone.0053529-Paxinos1" target="_blank">[66]</a> with a micro contusion in the cortex below impact site (black square). The right panel shows representative 10X-magnified images of Iba1-stained untreated WT and apoE−/− contused cortices. Microcontusions are denoted by black arrows. Note the pronounced localized activation of microglia around the contusion.</p

Loss of apoE exacerbates axonal injury after mrTBI.

<p>Axonal damage following mrTBI was assessed with silver staining (arrows). The left panel depicts representative images of silver-stained coronal sections at approximately −1.58 mm from bregma <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0053529#pone.0053529-Paxinos1" target="_blank">[66]</a> of untreated WT (<b>A</b>) and apoE−/− (<b>B</b>) mouse brains harvested at 7 d post-mrTBI. White matter areas with prominent silver staining are indicated by the black squares. Injury location is indicated by the arrowhead. The right panel (<b>C–L</b>) depicts representative 40x-magnified images of silver staining in five white matter areas in the brains of untreated WT (<b>C–G</b>) and apoE−/− (<b>H–L</b>) mice harvested at 7 d post-mrTBI.</p

ApoE is required for GW3965 to improve NOR performance after mrTBI.

<p>NOR memory was evaluated in untreated (V) and GW3965-treated (G) WT (<b>A</b>) and apoE −/− (<b>B</b>) mice at 2, 7, and 14 days post-mrTBI. Bars represent discrimination index (DI) scores. Cohorts were: sham (WT, n = 23, pooled; apoE−/−, n = 18, pooled) and 2 day (WT: untreated, n = 18, GW3965-treated, n = 15; apoE−/−: untreated, n = 10, GW3965-treated, n = 10), 7 day (WT: untreated, n = 13, GW3965-treated, n = 10; apoE−/−: untreated, n = 11, GW3965-treated, n = 11), and 14 day (WT: untreated, n = 14, GW3965-treated, n = 14; apoE−/−: untreated, n = 9, GW3965-treated, n = 9) post-mrTBI. DI scores were analyzed using two-way ANOVA and Bonferroni post hoc test. **: <i>p</i><0.01, ***: <i>p</i><0.001, ###: <i>p</i><0.001.</p

ApoE is required for GW3965 to suppress axonal damage after mrTBI.

<p>Silver-stained images of white matter areas in WT and apoE−/− brains were analyzed semiquantitatively using an arbitrary silver staining scale extending from 0 (<10% argyrophilic structures covering the image field) to 3 (>70% argyrophilic structures covering the image field). The bar graphs represent mean ± SEM silver stain intensity score (arbitrary value) of WT (<b>A–E</b>) and apoE−/− (<b>F–J</b>) brains in the corpus callosum (<b>A, F</b>), cingulum (<b>B, G</b>), external capsule (<b>C, H</b>), internal capsule (<b>D, I</b>), and optic tracts (<b>E, J</b>). Sample sizes were: sham, n = 6/genotype (pooled); untreated mrTBI, n = 5/time point/genotype; GW3965-treated mrTBI, n = 5/time point/genotype. Asterisks above individual bars indicate significant differences compared to the respective sham values (grey bars). *: <i>p</i><0.05, **: <i>p</i><0.01, ***: <i>p</i><0.001, ****: <i>p</i><0.0001. ### (<i>p</i><0.001) and #### (<i>p</i><0.0001) represent significant differences in silver stain scores between untreated WT and apoE−/− mice. § (<i>p</i><0.05), §§ (<i>p</i><0.01), §§§ (<i>p</i><0.001), and §§§§ (<i>p</i><0.0001) represent significant differences in silver stain scores between GW3965-treated WT and apoE−/− mice. Data were analyzed by two-way ANOVA followed by a Bonferroni post hoc test. Legend: V- untreated mice, open bars, G- GW3965-treated mice, black bars.</p